Direct Antimicrobial Activity of IFN-β

Kaplan, Amber; Lee, Michelle W.; Wolf, Andrea J.; Limon, Jose J.; Becker, Courtney; Ding, Minna; Murali, Ramachandran; Lee, Ernest Y.; Liu, George Y.; Wong, Gerard C. L.; Underhill, David

doi:10.4049/jimmunol.1601226

Cited by 54 publications

(45 citation statements)

References 41 publications

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“…Examples included members of the γ-chain-dependent IL family, along with type II IFNs. These results are consistent with unforeseen antimicrobial activities discovered in chemokines (2,4,26) and selected ILs (4,17,18,41,42). Of the ILs, sequences derived from turkey IL-5 (tIL-5) exhibited striking efficacy against all pathogens at pH simulating bloodstream (pH 7.5) and abscess (pH 5.5) environments.…”

Section: Discussionsupporting

confidence: 80%

Unifying structural signature of eukaryotic α-helical host defense peptides

Yount

Weaver

Lee

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Diversity of α-helical host defense peptides (αHDPs) contributes to immunity against a broad spectrum of pathogens via multiple functions. Thus, resolving common structure-function relationships among αHDPs is inherently difficult, even for artificial-intelligencebased methods that seek multifactorial trends rather than foundational principles. Here, bioinformatic and pattern recognition methods were applied to identify a unifying signature of eukaryotic αHDPs derived from amino acid sequence, biochemical, and threedimensional properties of known αHDPs. The signature formula contains a helical domain of 12 residues with a mean hydrophobic moment of 0.50 and favoring aliphatic over aromatic hydrophobes in 18-aa windows of peptides or proteins matching its semantic definition. The holistic α-core signature subsumes existing physicochemical properties of αHDPs, and converged strongly with predictions of an independent machine-learning-based classifier recognizing sequences inducing negative Gaussian curvature in target membranes. Queries using the α-core formula identified 93% of all annotated αHDPs in proteomic databases and retrieved all major αHDP families. Synthesis and antimicrobial assays confirmed efficacies of predicted sequences having no previously known antimicrobial activity. The unifying α-core signature establishes a foundational framework for discovering and understanding αHDPs encompassing diverse structural and mechanistic variations, and affords possibilities for deterministic design of antiinfectives.antimicrobial | host defense | antiinfective | amphipathic | bioinformatics A ntimicrobial host defense peptides (HDPs) are an evolutionarily ancient arm of host immunity that first arose in prokaryotes as a means to counter microbial competitors. Subsequently, such peptides evolved through adaptive radiation to exist in all classes of eukaryotes, where they continue to act in firstline defense against infection (1). Extensive studies have established that such peptides are not indiscriminant detergents, but rather have complex and multimodal mechanisms of action (2-4).As a group, α-helical HDPs (αHDPs) are among the most rapidly evolving molecules characterized to date. Moreover, genes encoding αHDPs are under strong positive selection, affording a high degree of mutational tolerance despite being limited by the biophysical constraints of an amphipathic helix (5-8). When compounded over an evolutionary timescale, this process has generated an exceptionally diverse repertoire of peptides capable of exerting multiple antimicrobial mechanisms. However, such diversity and context-dependent activity have also presented challenges to identifying common αHDP structure-activity relationships (SARs). While a number of groups have used computational or quantitative SAR (QSAR) methods, these efforts have largely focused on drug candidate optimization (9-12). As a result, other than charge or amphipathicity, resolving the unifying physicochemical requisites in three-dimensional space that confer antimicrobial ac...

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Section: Discussionsupporting

confidence: 80%

Unifying structural signature of eukaryotic α-helical host defense peptides

Yount

Weaver

Lee

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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“…In any case, the potential of Mtb to inhibit IFN- β -mediated NO production will be advantageous for the pathogen. We do not believe that the recently reported direct bactericidal effect of IFN- β (52) plays a role in our observed bactericidal effects since otherwise the Nos2 -/- cells should not be different from wild-type BMDM (Figure 1E).…”

Section: Discussionmentioning

confidence: 59%

Mycobacterium tuberculosisinhibits autocrine type I interferon signaling to increase intracellular survival

Banks

Ahlbrand

Hughitt

et al. 2018

Preprint

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SummaryThe type I interferons (IFN-α and -β) are important for host defense against viral infections. In contrast, their role in defense against non-viral pathogens is more ambiguous. Here we report that IFN-β-signaling in macrophages has protective capacity against Mycobacterium tuberculosis (Mtb) via the increased production of nitric oxide. Furthermore, Mtb is able to inhibit IFN-α/β-receptor-mediated cell signaling and the transcription of 309 IFN-β stimulated genes which includes genes associated with innate host cell defense. The molecular mechanism of inhibition by Mtb involves reduced phosphorylation of the IFNAR-associated protein kinases JAK1 and TYK2 leading to reduced phosphorylation of the downstream targets STAT1 and STAT2. Overall, our study supports the novel concept that Mtb evolved to inhibit autocrine type I IFN signaling in order to evade host defense mechanisms.

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“…In mammals, many antimicrobial proteins have highly antimicrobial regions, such as the fifth helical region of human and mouse IFN-β [36]. In this article, we noted that the grass carp CXCL20b exhibited a long N-terminal random region, which contained large amounts of basic amino acid residues ( Figure 6A).…”

Section: Discussionmentioning

confidence: 90%

Characterization and Antimicrobial Activity of the Teleost Chemokine CXCL20b

et al. 2020

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Fish are a potential source of diverse organic compounds with a broad spectrum of biological activities. Many fish-derived antimicrobial peptides and proteins are key components of the fish innate immune system. They are also potential candidates for development of new antimicrobial agents. CXCL20b is a grass carp (Ctenopharyngodon idella) CXC chemokine strongly transcribed at the early stage of bacterial infections, for which the immune role had not been reported to date. In the present study, we found that CXCL20b is a cationic amphipathic protein that displays potent antimicrobial activity against both Gram-positive and Gram-negative bacteria. The results of DiOC2(3) and atomic force microscopy (AFM) assays indicated that CXCL20b could induce bacterial membrane depolarization and disruption in a short time. By performing further structure-activity studies, we found that the antimicrobial activity of CXCL20b was mainly relative to the N-terminal random coil region. The central part of this cytokine representing β-sheet region was insoluble in water and the C-terminal α-helical region did not show an antimicrobial effect. The results presented in this article support the poorly understood function of CXCL20b, which fulfills an important role in bony fish antimicrobial immunity.

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Direct Antimicrobial Activity of IFN-β

Cited by 54 publications

References 41 publications

Unifying structural signature of eukaryotic α-helical host defense peptides

Unifying structural signature of eukaryotic α-helical host defense peptides

Mycobacterium tuberculosisinhibits autocrine type I interferon signaling to increase intracellular survival

Characterization and Antimicrobial Activity of the Teleost Chemokine CXCL20b

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